4-Penten-2-yl 6-(4-pentenyl-{62 -resorcylate dibenzyl ether

ABSTRACT

4-Penten-2-yl 6-(4-pentenyl)- Beta -resorcylate dibenzyl ether useful in preparing zearalone is disclosed. Zearalone is useful in promoting the growth rate of meat producing animals.

ite States Patent 11 1 Urry e11 311. 1 1 Jan. 28, 1975 [54] 4-PENTEN-2-YL 3.586.701 6/1971 Urrcy H 260 473 5 6 (4 PENTENYL B RESORCYLATE 3,631,179 12/1971 Urrey 260/473 5 DIBENZYL ETHER FOREIGN PATENTS OR APPLICATIONS [75] Inventors: Wilbert Herbert Urry, Chicago, 111.; 543376 1967 Germany 260/473 5 G Towns Mullenbach, Berkeley 1,337,167 1963 France 280/473 5 Calif- OTHER PUBLICATIONS [73] Assignee: Commercial Solvents Corporation Cram 6! g h mi ry,

. I N.Y., (1959), pp. 327-328. [22] Filed 1972 March, Advance Organic Chemistry," McGraw Hill [21] App]. No.: 247,414 Inc, (1968), N.Y., pg. 322.

Fieser et 211., Organic Chemistry," Reinhold Publ. 52 us. c1 ..260/473 R, 260/3432 F, (1956 page g 'g 8 3 38 Primary ExaminerL0rraine A. Weinberger 2 /47 26 l 2 /526 Assixtant Examiner-John F. Terapane 260/601 Attorney, Agent, or Firm- Morton, Bernard. Brown, [51] Int. Cl. c Roberts & Sutherkmd [58] Field of Search 260/473 R, 473 S H R f d [57] ABSTRACT e erences l e 4-Penten-2-y1 6-(4-pcntcny1)-B-resorcy1utc d1hcnzy1 UNITED STATES PATENTS ether useful in preparing zcarulonc is disclosed. Zcara- 31677-673 5/1954 M01115 c1111- H 260/473 5 lone is useful in promoting the growth rate of meat 3330,1159 7/1967 Dexter et a1 260/473 5 producing animuls 3.535.343 10/1970 Cross at 211.... 260/473 5 3,562,313 2/1971 Cross et a1 260/473 5 l Clfllm, N0 Drawings 1 4-PENTEN-2-YL 6-(4-PENTENYL-fi-RESORCYLATE DIBENZYL ETH ER BRIEF SUMMARY OF THE INVENTION HO (CH2)y wherein X is an integer having a value from 2 to 6 inclusive and Y is an integer having a value from 2 to 8 inclusive. More specifically the invention relates to a process for making all of the foregoing compounds by a new series of process steps utilizing new intermediate compounds.

it is an object of the present invention to provide a new means for synthesizing Zearalanone and related compounds.

It is another object of the invention to provide new intermediates useful in the preparation of Zearalanone and related compounds.

It is a further object of the invention to provide new processes for producing intermediate compounds useful in the synthesis of Zearalanone and related compounds.

DETAILED DESCRIPTION Zearalanone, whose synthesis is one of the objects of this invention, has the structure illustrated by the formula:

HO (CH2)4 An examination of the above formula reveals that it has one asymmetric carbon atom. Hence, this synthesis IO gives a mixture of two enantiomorphs designated as D and L by the older Fischer convention and by R and S by the newer convention ofCahn and lngold (Cahn, R. S. and lngold, C. K., J. Chem. Soc. 612, Cahn, R.S., J. Chem. Educ. 41, 116 (1964).

I5 Zearalanoen produced by the reduction of natural zearalenone has the same S configuration as does the parent compound. The chemical name for Zearalanone is: 6-(10-hydroxy--keto-undecyl)-,8-resorcylic acid lactone. Zearalanone was one of the compounds described and claimed in United States Letters Pat. No. 3,239,341 issued Mar. 8, 1966 to Hodge et al. The compound was prepared by the reduction of a natural product zearalenone, sometimes referred to as F.E.S. resulting from the fermentation of suitable nutrient media using the organism Gibberella zeae (Gordon) on deposit at the Northern Utilization Research and Development Division of the United States Department of Agriculture at Peoria, Illinois under the number NRRL-2830. The reduction was carried out by hydrogen under the influence of a catalyst such as palladium or platinum on char in a menstruum of ethyl alcohol (Tetrahedron Letters No. 27, pages 3109-3114, 1966).

The present invention is concerned with the discovery that Zearalanone can be made readily by the sequence of reactions illustrated in Chart l.

The first step in the sequence is the pyrolysis of 3-hydroxy-l,5-hexadiene to prepare S-hexenal which is reacted with malonic acid to form 2,7-octadienoic acid. The foregoing acid is esterified by treatment with diazomethane and the resulting methyl ester is reacted with the sodium salt of CHAR! I Gamma ethyl acetoacetate under the influence of sodium methoxide in a methanol menstruum to yield the sodium salt of methyl 6-(4-pentenyl)-B-dihydroresorcylate. The dihydroresorcylate sodium salt is then brominated at low temperature to form methyl 3-bromo-6-(4- pentenyl)-B-dihydroresorcylate which is dehydrobrominated by treatment with sodium ethoxide in an anhydrous ethanol menstruum to prepare ehtyl 6-(4-pentenyl)-B-resorcylate. The foregoing resorcylate is reacted with benzyl chloride to yield ethyl 6-(4-pentenyl)-B-resorcylate dibenzyl ether which is treated with the sodium alcoholate of 4-penten-2-ol to produce 4-penten-2-yl 6-(4-pentenyl)-B-resorcylate dibenzyl ether. The foregoing compound is treated successively with 2,3-dimethyl-2-butylborane, carbon monoxide, sodium acetate solution, and hydrogen peroxide to form zearalanone dibenzyl ether. On hydrogenation zearalanone dibenzyl ether is converted to (R,S)-zearalanone.

The foregoing sequence of reactions, as well as the reactions described in the specific example, can be carried out with appropriate starting materials to yield compounds related to (R,S)-zearalanone. They can be represented by the following formula:

HO (CH2)y Where X and Y are integers which can take the values:

X=2,3,4,5,or6.

Y=2,3,4,5,6,7,or8.

The values of X and Y for zearalanone are underscored.

For example, in order to prepare the compound where X 2 and Y= 2, it is necessary to start with acrolein (CH =CH-CHO) as Compound l of Chart I and to use the sodium alcoholate of 3-buten-2-ol in the reaction with the Compound lX (ethyl 6-(4-ethenyl)-B- resorcylate dibenzyl ether).

The compounds produced by the process of this invention are useful in promoting the growth rate of meat-producing animals. The compounds can be administered to animals by any suitable method including subcutaneous injection of pellets under the skin of the ears of mammals as well as by oral and parenteral administrations. For example, the compounds can be formulated into pellets and put under the skin of the ear by a suitable gun or they can be suspended in a medium such as peanut oil and injected parenterally. The compounds can also be blended with ordinary feed containing nutritional values in an amount sufficient to produce the desired rate of growth and can thus be fed directly to animals.

When the compounds are to be fed directly to animals, the feed composition can be prepared containing the usual nutritionally balanced quantities of fats, carbohydrates, proteins, vitamins, and minerals together with the chosen compound. Some of these usual dietary elements are grains, such as ground grain and grain byproducts; animal protein substances such as those found in fish meal and meat scraps; animal and vegetable fats; vegetable proteins like soybean oil meal or peanut oil meal; vitaminaceous materials, e.g. vitamin A and D mixtures; riboflavin supplements and other vitamin B complex members; antibiotic supplements such as zinc bacitracin feed grade; and bone meal and limestone to provide minerals. A type of conventional feed material for use with cattle includes alfalfa hay and ground corn cobs together with supplementary antibiotics and vitaminaceous materials if desired.

The amount of compound administered to the animal, of course, depends upon the specific animal. its age and sex, and the desired rate of growth. Usually. administration of from about l to about mg of a compound per animal per day produces significantly increased growth rate.

The following examples serve to illustrate the invention and set forth the best mode contemplated by the inventors for carrying out the invention.

The abbreviations used in the following examples are described in these paragraphs. The description of a nuclear magnetic resonance (nmr) scan is identified by the letters nmr followed by the solvent and reference substance placed in parenthesis; thus, nmr (CDCl TMS) means that the scan was made with deuterated chloroform as the solvent and tetramethylsilane as the reference substance. The position of the identified peaks may be described by the value:

8= cycles per second from TMS divided by 60 (This relation applies with a 60 megaherz instrument) 8 c.p.s. 60 or by 7': 10 minus 8 (10-8) 5,] singlet. one hydrogen 5.2 singlet, two hydrogens (1.1 doublet. one hydrogen t.2 triplet, two hydrogens m,4 multiplcl. four hydrogens broad 5.] a broad singlet for one hydrogen which may result from OH. COOH. CHO.

Coupling constants are valuable for identification of the positions of hydrogen atoms and with respect to variations ofthe electronic environments. The coupling constants are measured as the distance between the peaks in question on the x-axis of the scan and are re corded as J values in terms of c.p.s.

Cycles per second are denoted by c.p.s. and by Hz.

in all of the examples, the temperatures are in degrees centigrade. In the nmr data, TMS is tetramethylsilane; DSS is sodium 2,2-dimethyl-2-silapenlane-5- sulfonate.

In the following specific examples, the specific compounds used are such that in the general formulae presented herein X 3 and l 5. The specific reactions. however, are illustrative of the more general reactions when the compounds are generally represented with X being an integer of 2 to 6 (i.e. 2, 3, 4, 5 or 6) and Y being an integer of2 to 8 (i.e. 2, 3, 4, 5, 6, 7 or 8). in the following described general reactions the letter W and Z are also used to represent integers with W being an integer of from 0 to 6 (i.e. 0, l, 2, 3, 4, S or 6) and Z being an integer from 0 to 4 (i.e. 0, 1,2, 3 or 4). It should also be noted that a relationship exists between X and Z, such that when zearalanone or a related compound is described with the X in the general formula e.g. X= 3, the Z compound shoud be selected such that Z X 2 or in this illustration with X 3, Z would equal 1. Similarly, a relationship exists between W and Y, such that when a zearalanone or a related compound is described with the Y in the general formula e.g. l 5, the W compound should be selected such that W Y 2 or in this illustration with Y 5, W would equal 3.

EXAMPLE 1 This example illustrates the preparation of 5-hexenal l by the following reaction:

3-hydroxy-l 5-hexadiene 190 g, 1.94 mol, of 3;hydroxy-1,5-hexadiene was slowly distilled through a 50 cm column packed with 3 mm Pyrex helices maintained at 380. Fractional distillation of the pyrolysis mixture gave 1 11.2 g, 1.14 mol (59 percent), of 5-hexenal: bp 575 (57 mm); bp l2l (760 mm).

Although 5-hexenal is not a new compound, it is not readily available and, therefore, the above described step is a known method for the preparation of it.

EXAMPLE 2 This example illustrates the preparation of 2,7-

.octadienoic acid ll by the following general reaction A reaction mixture containing 76.9 g, 0.784 mol, of S-hexenal I, 90.0 g 0.865 mol, of malonic acid, and 145 ml of pyridine was stirred at under nitrogen for 60 hr. An additional 45.0 g of malonic acid was added to it, and stirring was continued for 24 hr at 25. It was then heated on a steam bath until carbon dioxide evolu- NaO CH3 ll CH tion-ceased (20 hr). Water (145 ml) was added to it, and the resulting mixture was extracted with ether (3 X 200 ml). The extract was washed with dilute hydrochloric acid (2N, 2 X ml), water (2 X 50 ml), and dried (Na SO Fractional distillation gave 83.0 g. 0.593 mol (76 percent), of ii: bp 86-87 (0.15 mm); nmr CDCl TMS) 612.34 (s, 1, COOH 7.26 and 6.98 2 t, 1, JAB 15.7 Hz, .lAX 7 Hz, CH. .Cl -I=CH), 5.97 and 5.70 (2 t, l, JAB =l5.7 Hz, JBX 1 Hz. CliCOO), 5.72, 4.92 and 4.88 (3 m, 3. Cll=CH). 2.12 (br m, 4, CH CH=CH and 1.60 ppm (br m. 2. CH C H CH Anal. Calcd. for C H O C. 68.6; H. 8.6. Found: C, 68.6; H, 8.7.

EXAMPLE 3 This example illustrates the preparation of methyl 2,7-octadienoate III by the following general reaction wherein W 3:

III

A solution of diazomethane in ether was added to a cold (0) solution of 83.0 g. 0.592 mol, of ll in 200 ml of ether until a yellow color persisted. Evaporation of the reaction mixture gave 90.3 g of crude III that was fractionally distilled to give 80.2 g, 0.520 mol (88 percent) oflll: bp 44-45 (0.70 mm); nmr (CDCI TMS) 87.04 and 6.78 (2 t, l, JAB 15.7 Hz, JAX 7 Hz, CH Clj=CH), 5.87 and 5.61 (2 t, l, JAB 15.7 Hz, JBX 1 H2, CflCO), 5.72, 4.92 and 4.88 (3 m. 3, Cl;l=CH2), 3.67 (s, 3, Q13), 2.l2 (br m. 4, gflgcH cHgL and (br "1, 2, Anal. Calcd. for C H O C, 70.2; H, 9.1. Found: C, 70.1; H, 9.2.

EXAMPLE 4 This example illustrates the preparation of sodium ethyl 6-(4-pentenyl)-B-dihydroresorcylate IV by the following general reaction wherein W 3:

o 0 ll NaO (CH2 w-CH=CH2 COOCH3 III IV HCl IV A 81.4 g, 0.626 mol, of freshly-distilled ethyl acetoacetate was added dropwise to a stirred solution of sodium ethoxide prepared from 14.4 g, 0.626 g-atom of sodium and 200 ml of ethanol under nitrogen. The resulting solution was held at reflux while 80.2 g, 0.521 mol, of III was added dropwise, and then such heating was continued with mechanical stirring for 22 hr. The solid that precipitated during the reaction and while the mixture was cooled to was removed on a filter, and it was washed with ether to give 110.80 g, 0.404 mol (78 percent), of white lV: nmr (D 0, DSS, integration of some ring hydrogen atoms not given since they exchanged) 85.72, 4.92 and 4.88 (3 m, 3 Q CH), 4.22 (q, 2, J 7 Hz, COOCfl 3.18 (d, J 10 Hz, flCCOO), 2.20 (m, OCQlj CH), 2.00 (br m, 2. (br m, 5, C*H(C H2)2-CH2), and l.26 ppm (t, 3, J= 7 Hz, CE

Then a solution of 3.00 g, 0.0109 mol, of [V in 50 ml of water was acidified with 3N hydrochloric acid and the resulting mixture was extracted with ether (4 X 25 ml). The extract was washed with water (4 X 25 ml), dried (MgSO and evaporated in a Rinco brand of vacuum rotary evaporator, a well known and widely lution of 32.3 g, 0.598 mol of sodium methoxide in I30 ml of methanol stirred under nitrogen, and then 74.2 g. 0.482 mol of [11 was also added dropwise. it was held at reflux with mechanical stirring for 20 hr. About 60 ml ofits solvent was removed under vacuum. and it was cooled to 0. A precipitate that formed during the above was removed on a filter and washed with ether until it was white to give 84.7 g, 0.326 mol (68 percent), of V: nmr (D 0. DSS, again exchange of hydrogen atoms on the ring occurred) 65.72. 4.92 and 4.88 (3 m, 3, Cl;l=C ;l2). 5.07 (s, OCCflCO). 3.18 (d. J 10 Hz, ljCCOO), 2.20 (m, OCCE CH), 2.00 (br m. 3. QB CH=CH and 1.33 ppm (br m, 5, CHKLlj- L Q The nmr spectrum is nearly the same as IV above except for the alkoxy absorptions.

The compound V may readily be acidified to prepare methyl 6-(4-pentenyl)-B-dihydroresorcylate VA by the following general reaction wherein W 3:

CLO-CH3 used vacuum rotary evaporator hereinafter referred to 7A as Rinco, to give a residue which crystallized from ligroin (bp 60-68) to give 2.37 g, 0.00942 mol (86 HO (CHZ)WCH=CHZ percent), of ethyl 6-(4-pentenyl)-B-dihydroresorcylate Meth l enten l) [V A: mp 72.5-73.5; nmr (coca, TMS) 512.32 (5, dihygmesorgylateywhen w 3 0.2, 2-0fl), 9.75 (s, 0.8, 40 5.72, 4.92 and 4.88 (3 m, 3, Cfl=Cfl- 5.52 (s, 0.8, 3CH), 4.29 and 4.22 (2 q, 2, J 7 Hz, COOCH 3.12 (s, 0.4, 3Cfl And in turn the compound VA may be reacted with 3.15 (d, 0.8, .l 10 Hz, lC l-1), 2.45 (m, ca. 2, sodium hydroxide to form V. Converting the sodium 5Cfl 2.06 (br m, 2, C H CH=CH 1.36 (br m, 5, salt V to VA and then treating VA with sodium hydrox- C l-1(C H CH and 1.29 ppm (t, 3, J 7 H2, CB ide to again form the sodium salt V, of course, provides Anal. Calcd, for C H O C, 66.7; H, 8.0. Found: C, an efficient method for preparing relatively pure V. 66.7; H, 8.0.

EXAMPLE 5 EXAMPLE 6 This example illustrates the preparation of methyl 6- This example illustrates the preparation of methyl 3- (4-pentenyl)-B-dihydroresorcylate sodium salt V by bromo-6-(4-pentenyl)-/3-dihydroresorcylate Vl by the the following general reaction wherein W 3: following general reaction wherein W 3:

O O O 0 ll I ll COCH3 Br C-OCl-l3 BIZ a NaO (CH2)w-CH=CH2 HO (Cllg)w-CH=CH2 V VI 0 CH2 0 O ll ll l ll C-OCHZCH3 (1H CO-CH3 ca (cHz)w CH ONa I u l /C fill-I NaO (CH2)WCH=CH2 NaO CH3 (III-I cooca III V The reaction mixture was prepared by dropwise addition of 70.7 g, 0.598 mol, of ethyl acetoacetate to a so- A solution of 58.2 g, 0.326 mol, of bromine and 193.1 g, l.87 mol, of sodium bromide in 200 ml of water was added dropwise over 6 hr to a rapidly stirred uct that was recrystallized from ligroin (60-68) to solution of 84.7 g, 0.326 mol, of V in 700 ml of water give 8.82 g, 0.0373 mol (55 percent). of pure Vll: mp cooled to After 30 min, the solid that had precipi- 55-56; nmr (CD Cl TMS) 811.83 (s, 1, hydrogen tated was removed by filtration. It was dissolved in 200 bonded 2-Ofl), 6.90 (s, 1,4-Ofl), 6.33 and 6.30 (2 ml of ether, and the resulting solution was washed with d, 2, J 2 Hz, aromatic Cl l), 5.72, 4.92 and 4.88 (3 water (3 X 150 ml), and briefly dried (MgSO it was m, 3, CH=CH 3.82 (s, 3, CH 2.82 (t. 2, J 7 Hz. evaporated (Rinco, 25), and the residue was recrystal- ArC h 2.08 (br m, 2, Cfi CH=CH and 1.64 ppm lized from 200 ml of ether and pentane to give 70.4 g, (br m, 2, CH C l-l CH Anal. Calcd. for C H O C, 0.222 mol (68 percent), of white crystalline V1: mp 66.2; H, 6.8. Found: C, 66.1; H, 6.7. 91-93; nmr (CDCl TMS) 68.10 (s, l, 4-Ol;l), In Example 7, the de-hydrobromination of com- 5.72. 4.92 and 4.88 (3 m, 3. Clj=Cfl 3.77 (s, 3, pound Vl can be effected at temperatures in the range H.1).3,35(d, 1,J= 10 Hz, HCCOO), 2,72 (dd, 1 JAB 60Cl20C but a temperature near 65C is preferred. 20.4 Hz. .IAX 11.0 Hz. OCQ-hCH). 2.43 (dd, 1, The de-hydrobromination step could be carried out JAB 204 HZ JBX g HZ OCCHZCH) 2,0 b in a menstruu'm of an alcohol other an methanol, for m, 2. Qil CH=CH and 1.45 ppm (br m, 5, example ethanol or butanol. ll(Qfl CH Anal. Calcd. for C H o Brz C, 49.2;

H, 5.4; B1, 25.2. Found: c, 48.9; H, 5.7; B1, 25.2. EXAMPLE 8 In Example 8 temperature at which the reaction This example illustrates the preparation of ethyl of bromine with Compound V is allowed to occur is 6-(4-pentenyl)-B-resorcylate Vlll by the following genkept at 0C in order to minimize the reaction of broeral reaction wherein W 3 and R ethyl:

l if I Br COCH3 C-OR RONa 8 HO (CH2 w-CH=CH2 HO (CH2 CH=CH2 VI VIII mine with the double bond in the side chain of the com- A solution containing 19.33 g, 0.0610 mol, of V1, and

pound. Temperatures up to C could be used for this sodium ethoxide (prepared from 9.00 g, 0.391 g-atom, reaction but 0C is preferred. A lower temperature of sodium and in the 250 ml of ethanol) was held at relimit of about l0C is set since the rate of the desired flux un er nitr g n f 6 and then it was evaporated reaction becomes too low at temperatures much b l w under vacuum until its volume was about 100 m1. it was l0C and because the reaction mixture f e diluted with water to 300 ml, and acidified with sulfuric EXAMPLE 7 acid (6N) while it was held at 0. The resulting mixture was extracted with ether (3 X 150 ml). The extract was This example illustrates the preparation of methyl then washed with water (4 X 100 ml), decolorized with 6-(4pentenyl-B-resorcylate VIl by the following gen charcoal, and evaporated (Rinco) to yeild 14.0 g,

eral reaction wherein W 3 and R methyl: 0.0562 mol (92 percent), of crude Vlll. Dry column 0 O OH 0 Br ZOCH3 0 OR RONa HO (CH2)w-CH=CH2 HO (CH2)w-CH=CH2 VI VII R methyl or ethyl A solution of 21.5 g, 0.0678 mole, of VI and sodium chromatography (300 g Silica Gel H, 10 percent ethyl methoxide (prepared from 15.6 g, 0.678 g-atom of soether in methylene chloride) gave 9.15 g, 0.0366 mol dium) in 350 ml of anhydrous methanol was main- P n nmr s. 511-95 1, tained at reflux under nitrogen for 9 hr. Then 200 ml H), H) and of methanol was evaporated under vacuum. The reac- 60 2 H m c E), and tion mixture was held at 0 while enough water to give 5 15), (q. 7 HZ, EZ). 400 ml of the mixture was added to it. It was acidified J: 7 H2, QL Z), 2, 2 z). with sulfuric acid (6 N), and extracted with ether (3 X m, i 2 2 2)i and PP (L J: 7 53)- 200 ml). The extract was washed with water (4 x 200 Except for the expected differences, this nmr spectrum ml). Then it was decolorized with charcoal, and evapo- 5 is the Same as that of rated (Rinco) to yield 14.9 g, 0.0632 mol (93 percent), of crude Vll. Purification by dry column chromatogra- EXAMPLE 9 phy (300 g, Silica Gel H, 10 percent ethyl ether in This example illustrates the preparation of ethyl methylene chloride) yielded fractions that gave prod- 6-(4-pentenyl)-B-resorcylate dibenzyl ether [X by the 11 following general reaction wherein W 3 and R ethyl:

VIII

A mixture of 31.5 g, 0.126 mol, Vlll, 60.5 g of anhydrous potassium carbonate, and 31.5 ml 0.274 mol, of benzyl chloride in 300 ml of dimethylsulfoxide was stirred on a steam bath for 6 hr. 1.0 1 of water was added to it while it was stirred, and then it was held overnight at -15. The product that had crystallized was collected on a filter, and it was recrystallized from a mixture of ethyl ether and ligroin (bp 6068) to give 45.5 g, 0.106 mo] (84 percent), oflX: mp 4951;nmr (CDC1 TMS) 87.32 (m, 10, C 11 6.44 (s, 2, aromatic Cl;l), 5.72, 4.92 and 4.88 (3 m, 3, Cfl=Cfl 4.98 and 4.96 (2 s, 4, C H Qfl 4.28 (q, 2, J= 7 HZ, COOCfl-z), 2.58 (t, 2, J 71-12, ArC z), 2.00 (m, 2, C H CH=CH 1.64 (br n1, 2, CH Cfl CH- and 1.23 ppm (t, 3,J=7 Hz, Chis). Anal. Calcd. for C ,,H O 78.2KB, 7.0. Found: c, 78.0; H, 6.9.

EXAMPLE 10 This example illustrates the preparation of 4-penten- 2-yl 6-(4-pentenyl)-B-resorcylate dibenzyl ether X by the following general reaction wherein W= 3, R ethyl and Z l.

0.97 g 0.042 mol, of sodium was added to a solution of 10.0 ml of 4-penten-2-ol (dried by distillation from its sodium alkoxide) in ml oftoluene (dried by distillation from sodium). The reaction mixture was stirred at under nitrogen until the sodium had been consumed. Then 6.00 g, 0.0140 mol of IX (thoroughly dried under high vacuum at 55 is 10 ml of toluene was added to it, and it was stirred at 100 under nitrogen for 36 hr. The brown reaction mixture was held at 0 while it was acidified with dilute hydrochloric acid. The organic layer was separated, and was washed with water (3 X 50 ml), decolorized with charcoal. and dried (MgSO Evaporation (Rinco) gave a residue that was pruified by dry column chromatography g of Silica Gel H, 10 percent ethyl ether in methylene chloride) to give 4.68 g, 0.00995 mol (71 percent). of X. Sublimation of this product gave pure X: nmr (CDCl TMS)67.32(m,10,C fl 6.46 and 6.43 (2 s, 2. aromatic Clj), 5.72, 4.92 and 4.88 (3 m, 6. Cl l=Cl l 5.25 (br m, 1, COOCfl), 5.01 and 4.99 (2 s. 4. C H Qfl 2.60 (t, 2, J 7 Hz, ArQfl 2.00 (br m. 4. Cfl CH=CH 1.70 (br m, 2, CH gfl cH and 1.22 ppm (d, 3, J= 6.5 Hz, Cfl Anal. Calcd. for C ,H ,O,: C, 79.2; H, 7.3. Found: C, 79.4; H, 7.2.

EXAMPLE 11 This example illustrates the preparation of zearalanone dibenzyl ether XI by the following general reaction wherein W= 3, X= 3, Y= and Z= 1.

injected in rapid succession. The reaction mixture was then stirred at 50 for 7 hr. It was evaporated (Rinco), and the organic residue was dissolved in ether. This solution was washed with saturated potassium carbonate A solution ofX in 60 ml of ether was freed of peroxides by vigorously shaking it for 5 min with 60 ml of a solution prepared from 60 g of FeSO 7H O and 6.0 ml of concentrated sulfuric acid in 110 ml of water. The ether solution was then washed with water (l X 30 ml), 5 percent sodium hydroxide (l X 30 ml), and water (5 X 30 ml). It was dried (MgSO evaporated (Rinco), and held under high vacuum at 50 for 24 hr.

Then, a solution of 1.39 g, 2.95 X 10" mol, of this X in 80 ml of tetrahydrofuran (distilled from calcium hydride) was injected into a 100 ml, one neck round bottom flask equipped with efficient magnetic stirring, a rubber septum cap, and a nitrogen seal connected via a large-bore hypodermic needle in the septum. 6.96 ml, 0.00295 mol, of 0.424 M 2,3-dimethyI-Z-butylborane in tetrahydrofuran was then injected dropwise into the reaction mixture that was stirred at 0, according to the following schedule: 0 hr, 2.40 ml, over 10 min; 0.5 hr, 4.30 ml, over 10 min; 53.5 hr, 0.26 ml, over 2 min. The temperature was maintained at C except during these additions. After 140 hr of stirring at 25, 0.106 ml, 5.90 X 10 mol, of water was injected, a large-bore hypodermic needle was placed through the septum cap, and the flask was then sealed in a high pressure auto- I clave that had been thoroughly flushed with carbon monoxide. The autoclave was maintained at 88 atm of carbon monoxide (C.P.) pressure, and at 60 for 11 hr while it was continually rocked. Then it was slowly vented, and the reaction mixture was again placed under a nitrogen seal. It was held at 25 with rapid stirring while 1.19 ml, 0.00357 mol, of 3.0 M sodium acetate, and 1.19 ml of percent hydrogen peroxide were (1X15 ml), and water (3 X 15 ml), dried (Na SO and evaporated (Rinco) to give 1.37 g of viscous residue that was separated by dry column chromatography (40 g of Silica Gel H containing 15 percent water; 10 percent ethyl acetate in benzene) to yield ca. 0.19 g, 0.00038 mol (13 percent), pure Xl: mp l03-l05; nmr CDCl TMS) 87.35 (m, 10, C fl 6.43 (s, 2, aromatic CH), 5.24 (br m, l, COOCfl), 5.01 and 4.98 (2 s, 4, benzyl CH2), 2.58 (br m, 2, ArCH- 2.37 (t, 4,J 6.0 Hz, QH COCH 1.50 (br m, 10, ((JQ CH COCHACHQ and 1.13 ppm (d, 3, J= 6.5 Hz, Cfl mass spectrum eV) m/e (rel intensity) 500 (6), 482(2), 409(2), 391(2), 181(6), 91(100), 69(2), 65(4), 32(2), 28(8). The nmr and mass spectra are identical to those of the dibenzyl ether of zearalanone prepared from natural zearalenone. The melting point is the same as that of X1 prepared via other sequences, and mixed melting points are not depressed.

ln Example 11, the reaction between Compound X and 2,3-dimethyl-2-butylborane was carried out at 25C. This temperature can be raised to 50C but yields fall off beyond this value. Temperatures much lower than 25C are not practical since the rate of reaction is too low at the lower temperatures.

The reaction with carbon monoxide can be carried out at temperatures above 60C, but the yields will be lower ifthis value is exceeded by say 20C. Lower temperatures, e.g. down to room temperature. can be used if longer reaction times can be tolerated. An increase in carbon monoxide pressure will, of course, increase the reaction rate and make lower temperatures more acceptable.

1. EXAMPLE 12 This example illustrates the preparation of DL- zearalanone Xll by the following general reaction wherein X 3 and Y= 5:

H2, Pd on charcoal DL-Zearalanone when X (R,S) zearalanone A solution of 0.100 g, 0.0002 mol, of XI in 10.0 ml of ethyl acetate and 4.0 ml of absolute ethanol with 0.05 g of percent palladium on charcoal catalyst and three drops of triethylamine added was hydrogenated at 1 atm until hydrogen consumption ceased. The reaction mixture was then filtered and evaporated (Rinco), and the residue was purified by preparative thin layer chromatography (Silica Gel, 10 percent ethyl acetate in benzene to give 0.054 g, 0.000169 mo] (84 percent), of XII: mp 2082l0 (from acetone); nmr (acetone-d TMS) 811.87 (br s, l, Z-Ofl), 6.32 (d, l, J 2.5 Hz, aromatic Cfl), 6.28 (d, l, J 2.5 Hz, aromatic CB), 7.34 (br s, l, 4Ofl), 5.20 (br m, l, COOCli), 3.02 and 2.74 (2 br m, 6, ArCfl and 05200952). 2.50 to l.20 (very br m, 10, CH (Cfl CH and CH(C H CH and 1.32 ppm (d, 3, J= 6.0 Hz. CB mass spectrum eV) m/e (rel intensity) 320(35), 302(l9), 251(19), 177(36), l63(98), 150(35), 69(46), 55(76), 4l( These nmr and mass spectra are identical to those of naturally-derived S- zearalanone.

in Example 12, a palladium-on-charcoal catalyst is used for replacing the benzyl groups with hydrogen atoms. Other mild hydrogenation catalysts such as platinum-on-charcoal can be used for this purpose.

What is claimed is:

l. The compound 4-penten-2-yl 6-(4-pentenyl)-B- resorcylate dibenzyl ether having the formula 

